Angelique Micro, 0.25 mg+0.5 mg, film-coated tablets, 28 pcs.

Angelique Micro, 0.25 mg+0.5 mg, film-coated tablets, 28 pcs.

Angeliq® Micro is not used for contraception.

If you suspect pregnancy, you should stop taking the pills until pregnancy has been ruled out (see “Use during pregnancy and lactation”).

If any of the following conditions/diseases or risk factors are present or worsened, before starting or continuing to take Angeliq® Micro, you should evaluate the individual risk-benefit ratio of treatment, taking into account the possible need to discontinue it.

When prescribing HRT to women who have several risk factors for the development of thrombosis or a high degree of severity of one of the risk factors, the possibility of mutually enhancing the effect of risk factors and the prescribed treatment on the development of thrombosis should be taken into account. In such cases, the total value of the existing risk factors increases. If there is a high risk, Angeliq® Micro is contraindicated.

VTE

A number of controlled randomized and epidemiological studies have revealed an increased relative risk of developing VTE, i.e. deep vein thrombosis or pulmonary embolism, against the background of HRT. Therefore, when prescribing Angeliq® Micro to women with risk factors for VTE, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

High risk factors for developing VTE include individual and family history (the presence of VTE in close relatives at a relatively young age may indicate a genetic predisposition) and obesity with a BMI of more than 30 kg/m2. The risk of VTE also increases with age. The possible role of varicose veins in the development of VTE remains controversial.

The risk of VTE may temporarily increase with prolonged immobilization, major elective and post-traumatic surgery, or major trauma. In case of prolonged immobilization or planned surgery, the drug should be stopped 4–6 weeks before surgery; resumption of use is possible only after the woman’s motor activity has been completely restored.

Treatment should be stopped immediately if symptoms of thrombotic disorders appear or their occurrence is suspected.

It is necessary to assess the ratio of individual risk and benefit of treatment in women using HRT drugs in conjunction with anticoagulants.

Arterial thromboembolism

Randomized controlled trials with long-term use of CCE and MPA did not provide evidence of a positive effect on the cardiovascular system. Large-scale clinical studies of the combination of CCE and MPA revealed a possible increase in the risk of coronary heart disease in the first year of use, followed by a lack of positive effect. One large clinical trial using CBE alone found a potential reduction in the incidence of CAD among women aged 50–59 years, but no overall benefit in the overall study population. As a secondary outcome, two large clinical trials using CCE either alone or in combination with MPA found a 30–40% increased risk of stroke. It is therefore unknown whether this increased risk applies to HRT products containing other types of estrogens and progestogens or to non-oral routes of administration.

Endometrial cancer

With long-term estrogen monotherapy, the risk of developing endometrial hyperplasia or carcinoma increases. The addition of drospirenone prevents the development of endometrial hyperplasia caused by estrogen. If there is a history of endometrial hyperplasia, estrogens alone or in combination with gestagens should be used with caution.

Mammary cancer

Clinical and observational studies have found an increase in the relative risk of developing breast cancer in women using HRT for several years. This may be due to earlier diagnosis, accelerated growth of an existing tumor during HRT, or a combination of both factors. The relative risk increases with duration of therapy but may be absent or reduced with estrogen-only treatment. This increase is comparable to the increased risk of breast cancer in women with a later onset of natural menopause, as well as with obesity and alcohol abuse. The increased risk gradually decreases to normal levels over several years after stopping HRT.

The increased risk of breast cancer has been suggested based on the results of more than 50 epidemiological studies (risk ranges from 1 to 2).

Two large randomized trials of CBE alone or in combination with MPA reported estimated risk ratios of 0.77 (95% CI 0.59–1.01) or 1.24 (95% CI 1.01) -1.54) after approximately 6 years of HRT use. It is unknown whether this increased risk also applies to other HRT drugs.

HRT increases mammographic breast density, which in some cases may have a negative effect on X-ray detection of breast cancer.

When prescribing Angeliq® Micro to women with risk factors for the occurrence of estrogen-dependent tumors (for example, first-degree relatives with breast cancer), the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

Ovarian cancer

Ovarian cancer is less common in the population than breast cancer. A meta-analysis of 52 epidemiological studies suggests a slight increase in the relative risk of developing ovarian cancer in women treated with HRT compared with women never treated (prospective studies: RR 1.2, 95% CI 1.15–1.26 ; all studies: RR 1.14, 95% CI 1.1–1.19). Women continuing to take hormone replacement therapy had a slightly increased risk of developing ovarian cancer (RR 1.43, 95% CI 1.31–1.56).

Other studies, including the WHI

, indicate that the use of combination drugs for HRT may be associated with a similar or slightly lower risk, but the risk may be more significant with long-term use (over several years).

Liver tumor

During the use of sex hormones, which also include drugs for HRT, benign and even more rarely malignant liver tumors have been observed in rare cases. In some cases, these tumors have led to intra-abdominal bleeding, which is life-threatening. If there is pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding, the differential diagnosis should take into account the possibility of a liver tumor.

Cholelithiasis

It is known that estrogens increase the lithogenicity of bile. The risk of developing cholelithiasis increases 2–4 times when treated with estrogen.

Dementia

There is limited clinical trial data on a possible increased risk of dementia in women starting CEE-containing medications aged 65 years or older. As observed in studies, the risk may be reduced if HRT preparations containing CEE are started in early menopause.

Other conditions/diseases

Treatment should be stopped immediately if migraine-like pain or frequent and unusually severe headaches appear for the first time, as well as if other symptoms appear that are possible precursors of a thrombotic stroke of the brain.

The relationship between HRT and the development of clinically significant arterial hypertension has not been established. A slight increase in blood pressure has been described in women taking HRT; clinically significant increases are rare. However, in some cases, if persistent clinically significant arterial hypertension develops while taking HRT, discontinuation of HRT may be considered. In women with high blood pressure, there may be a slight decrease in blood pressure while taking the drug Angeliq®. In women with normal blood pressure, there are no significant changes in blood pressure.

Kidney failure.

In renal failure, the ability to excrete potassium may be reduced. Taking drospirenone does not affect the concentration of potassium in the blood plasma in patients with mild to moderate forms of renal failure. The risk of developing hyperkalemia cannot theoretically be excluded only in the group of patients in whom the concentration of potassium in the blood plasma before treatment was determined at ULN, and who additionally take potassium-sparing drugs.

Liver dysfunction.

For mild liver dysfunction, incl. Various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, require medical supervision, as well as periodic liver function tests.

If liver function indicators deteriorate, Angeliq® Micro should be discontinued.

In case of recurrence of cholestatic jaundice or cholestatic itching, observed for the first time during pregnancy or previous treatment with sex hormones, taking Angeliq® Micro should be stopped immediately.

Special monitoring of women is necessary when triglyceride concentrations increase. In such cases, the use of HRT may cause a further increase in the concentration of triglycerides in the blood, which increases the risk of acute pancreatitis.

Although 3HT may affect peripheral insulin resistance and glucose tolerance, there is usually no need to change the treatment regimen of diabetic patients when undergoing HRT. However, women with diabetes should be monitored when undergoing HRT.

Some patients may develop unwanted effects of estrogen stimulation, such as abnormal uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for examination of the endometrium in order to exclude an organic disease.

Under the influence of estrogens, uterine fibroids can increase in size. In this case, treatment should be stopped.

It is recommended to discontinue treatment if endometriosis relapses during HRT. If prolactinoma is suspected, this disease should be excluded before starting treatment. If prolactinoma is detected, the patient should be under close medical supervision (including periodic assessment of prolactin concentrations).

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. During treatment with Angeliq® Micro, women prone to chloasma should avoid prolonged exposure to the sun or UV radiation.

The following conditions/diseases may occur or worsen during HRT, and women with these conditions/diseases should be under medical supervision when undergoing HRT: epilepsy; benign breast tumor; bronchial asthma; migraine; porphyria; otosclerosis; systemic lupus erythematosus; chorea.

In women with hereditary forms of angioedema, exogenous estrogens may cause or worsen symptoms of angioedema.

Preclinical safety data.

Preclinical data from routine repeated-dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity studies do not indicate a particular risk to humans. However, it should be remembered that sex hormones can promote the growth of certain hormone-dependent tissues and tumors.

Medical examination and consultation.

Before starting or resuming taking Angeliq® Micro, you should familiarize yourself in detail with the patient’s medical history and conduct a general medical and gynecological examination. The frequency and nature of such examinations should be based on existing standards of medical practice with the necessary consideration of the individual characteristics of each patient (but not less than once every 6 months) and include measurement of blood pressure, assessment of the condition of the mammary glands, abdominal and pelvic organs, including cytological examination cervical epithelium.

Impact on the ability to drive vehicles and machinery.

Not found.

Compound

Overdose

Acute toxicity studies have not revealed a risk of acute side effects when accidentally taking the drug in quantities many times higher than the daily therapeutic dose.

In clinical studies, the use of drospirenone up to 100 mg or combined estrogen/progestin drugs containing 4 mg estradiol was well tolerated. Symptoms that may occur in case of overdose: nausea, vomiting, vaginal bleeding. There is no specific antidote, treatment is symptomatic.

Directions for use and doses

Orally, regardless of food intake, swallow whole, with a small amount of liquid.

If a woman does not take estrogens or switches to Angeliq® Micro from another combination drug for continuous use, she can begin treatment at any time. Patients who switch to Angeliq® Micro from a combination drug for a cyclic HRT regimen should begin taking it after the end of the current cycle of therapy.

Each package is designed for 28 days of use.

You should take 1 tablet daily. After finishing taking 28 tablets. from the current package, the next day they begin taking tablets from a new package of Angeliq® Micro (continuous HRT), taking the first tablet on the same day of the week as the first tablet from the previous package.

The time of day a woman takes the drug does not matter, but if she starts taking the pills at a specific time, she should continue to do so at that time. The forgotten pill should be taken as soon as possible. If more than 24 hours have passed after the usual dosing time, you should not take an additional tablet. If you miss several tablets, you may develop bleeding from the vagina.

Use in certain patient groups

In children. The drug is contraindicated for use in children and adolescents under 18 years of age.

In the elderly. There are no data indicating the need for dose adjustment in elderly patients. Information on the use of the drug in women aged 65 years and older is presented in the “Special Instructions” section.

For liver dysfunction. In women with mild to moderate liver dysfunction, drospirenone is well tolerated. The drug is contraindicated for use in women with severe liver dysfunction (see “Contraindications”).

For renal dysfunction. A small increase in drospirenone exposure was observed in women with mild to moderate renal impairment but is not expected to be clinically significant. The drug is contraindicated for use in women with severe renal impairment (see “Contraindications”).

Interaction

Long-term treatment with drugs that induce liver enzymes (for example, some anticonvulsants and antimicrobial drugs) can increase the clearance of sex hormones and reduce their clinical effectiveness, which is manifested by irregular bleeding. A similar property to induce liver enzymes has been found in hydantoins, barbiturates, primidone, carbamazepine and rifampicin, and the presence of this feature is also suggested in oxcarbazepine, topiramate, felbamate and griseofulvin. Maximum enzyme induction is usually observed no earlier than 2–3 weeks, but may then persist for at least 4 weeks after discontinuation of the drug.

In rare cases, during concomitant use of certain antibiotics (for example, penicillin and tetracycline groups), a decrease in the concentration of estradiol was observed.

The main metabolites of drospirenone are formed in plasma without the participation of the cytochrome P450 system. Therefore, the effect of inhibitors of the cytochrome P450 system on the metabolism of drospirenone is unlikely. However, CYP3A4 inhibitors (eg cimetidine, ketoconazole, etc.) may inhibit the metabolism of estradiol.

Interaction of the drug Angeliq® Micro with other drugs

Based on in vitro interaction studies, as well as an in vivo study in female volunteers taking 3 mg of drospirenone per day in combination with omeprazole, simvastatin or midazolam, it can be concluded that a clinically significant interaction of drospirenone with cytochrome P450 on the metabolism of other medicinal substances is unlikely.

Pharmacodynamic interaction with antihypertensive drugs and NSAIDs

An increase in serum potassium concentration when taking Angeliq® Micro and NSAIDs or antihypertensive drugs in combination is unlikely. The combined use of the above three types of drugs may lead to a slight increase in serum potassium concentrations, more pronounced in women with diabetes mellitus.

Interaction with alcohol

Excessive alcohol consumption during HRT may increase circulating estradiol concentrations.

Pharmacodynamics

The drug Angeliq® Micro contains 17β-estradiol, chemically and biologically identical to endogenous human estradiol, and the synthetic progestogen drospirenone. 17β-estradiol provides hormone replacement during and after menopause. The addition of drospirenone provides control of bleeding and counteracts the development of estrogen-induced endometrial hyperplasia.

Effects of estradiol

The decline of ovarian function, accompanied by a decrease in the production of estrogen and progesterone, leads to the development of menopausal syndrome, which is characterized by vasomotor and organic symptoms. Hormone replacement therapy (HRT) is indicated to treat these symptoms.

Of all natural estrogens, estradiol is the most active and has the greatest affinity (binding strength) for estrogen receptors. Target organs for estrogen include, but are not limited to, the uterus, hypothalamus, pituitary gland, vagina, mammary glands, and bones (osteoclasts).

Other effects of estrogens include reductions in blood insulin and glucose concentrations, receptor-mediated vasoactive effects, and receptor-independent effects on vascular smooth muscle cells. Estrogen receptors have been identified in the heart and coronary arteries.

Oral administration of natural estrogens has advantages in cases of hypercholesterolemia due to a more favorable effect on lipid metabolism in the liver.

Estrogen monotherapy has a dose-dependent stimulating effect on endometrial mitosis and proliferation and, thus, increases the incidence of endometrial hyperplasia and, consequently, the risk of developing endometrial cancer. To avoid the development of endometrial hyperplasia, a combination with progestogens is necessary.

Effects of drospirenone

Drospirenone has pharmacodynamic effects very similar to natural progesterone.

Progestogenic activity

Drospirenone is a potent progestogen with a central inhibitory effect on the hypothalamic-pituitary-gonadal axis. In women of reproductive age, drospirenone has a contraceptive effect; When drospirenone is administered as a single drug, ovulation is suppressed. The threshold dose of drospirenone to suppress ovulation is 2 mg/day. Complete transformation of the endometrium previously exposed to estrogen occurs after taking a dose of 4 or 6 mg/day for 10 days (=40–60 mg per cycle). Continuous hormone replacement therapy with Angeliq® Micro allows you to avoid regular withdrawal bleeding, which is observed with cyclic or phase HRT. During the first months of treatment, bleeding and spotting are quite common, but their frequency decreases over time.

Antimineralocorticoid activity

Drospirenone has the ability to competitively antagonize aldosterone. Women who received drospirenone in addition to estradiol in a clinical study reported less peripheral edema than those who took estradiol alone.

Antiandrogenic activity

Like natural progesterone, drospirenone has antiandrogenic properties.

Effect on carbohydrate metabolism

Drospirenone has neither glucocorticoid nor antiglucocorticoid activity and does not affect glucose tolerance or insulin resistance. When using the drug Angeliq® Micro, glucose tolerance is not impaired.

Other properties

Observational studies suggest that among postmenopausal women, the incidence of colon cancer is reduced when using HRT. The mechanism of action is still unclear.

Pharmacokinetics

Estradiol

Absorption

After oral administration, estradiol is quickly and completely absorbed. During absorption and first passage through the liver, estradiol undergoes significant metabolization, for example into estrone, estriol and estrone sulfate. After oral administration, the bioavailability of estradiol is about 5%. Cmax of estradiol in plasma, approximately 16 pg/ml, is usually achieved 28 hours after taking the tablet. Food intake does not affect the bioavailability of estradiol.

Distribution

After oral administration of the drug Angeliq® Micro, a gradual change in the concentration of estradiol in the blood plasma is observed over 24 hours. Due to the circulation of estrogen sulfates and glucuronides in a wide range on the one hand, enterohepatic recirculation on the other, T1/2 of estradiol is a complex parameter , which depends on all these processes and is in the range of 13–20 hours after ingestion.

Estradiol binds nonspecifically to serum albumin and specifically to SHBG. The free fraction of estradiol in plasma is approximately 1–2%, and the fraction of the substance bound by SHBG is in the range of 40–45%. After oral administration, estradiol causes the formation of SHBG, which affects the distribution of serum proteins, causing an increase in the SHBG-bound fraction and a decrease in the albumin-bound and unbound fractions, indicating the non-linearity of the pharmacokinetics of estradiol after taking the drug Angeliq® Micro. The apparent Vd of estradiol after a single intravenous injection is about 1 l/kg.

Metabolism

Estradiol is metabolized primarily in the liver, and also partially in the intestines, kidneys, skeletal muscles and target organs. These processes are accompanied by the formation of estrone, estriol, catechol estrogens, as well as sulfate and glucuronide conjugates of these compounds, each of which has significantly less estrogenic activity or no estrogenic activity at all. Plasma estrone concentrations are 6 times higher than estradiol. Plasma concentrations of estrone conjugates are 26 times higher than the corresponding concentrations of free estrone.

Elimination

Estradiol clearance from plasma is about 30 ml/min/kg. Estradiol metabolites are excreted by the kidneys and through the intestines with a T1/2 of approximately 24 hours.

Css

With daily use of the drug Angeliq® Micro Css of estradiol in the blood plasma is achieved after approximately 5 days. On average, the concentration of estradiol in blood plasma ranges from 12 pg/ml (minimum level) to 29 pg/ml (maximum level).

Drospirenone

Absorption

After oral administration, drospirenone is rapidly and completely absorbed. Bioavailability after oral administration is 76–85%. Food intake does not affect the bioavailability of drospirenone.

Distribution

Cmax of drospirenone in plasma, approximately 3.35 ng/ml, is achieved approximately 1 hour after single and multiple doses of 0.25 mg of drospirenone. After this, a biphasic decrease in the concentration of drospirenone in plasma is observed with a final T1/2 of about 35–39 hours. Drospirenone binds to serum albumin and does not bind to SHBG and corticoid-binding globulin. About 3–5% of the total plasma concentration of drospirenone is not bound to protein.

Metabolism

After oral administration, drospirenone is largely metabolized. The main metabolites in human plasma are the acid form of drospirenone and 4,5-dihydro-drospirenone-3-sulfate. Both metabolites are formed without the participation of the cytochrome P450 system. Based on in vitro data, drospirenone is slightly metabolized by the cytochrome P4503A4 system.

Elimination

Plasma clearance of drospirenone is 1.2–1.5 ml/min/kg. Some of the dose received is excreted unchanged. Most of the dose is excreted by the kidneys and through the intestines in the form of metabolites in a ratio of 1.2:1.4 with T1/2 of about 40 hours.

Css

Achieved after approximately 10 days of daily use of the drug Angeliq® Micro. Due to the long T1/2 of drospirenone, Css is 2-3 times higher than the concentration after a single dose.